Molecular Genetics of Nail–Patella Syndrome


Nail–patella Syndrome (NPS) is a pleiotropic disorder affecting development of the limbs, kidneys, eyes and central nervous system, which is the result of heterozygous, loss‐of‐function mutations in the transcription factor, LIM‐homeobox 1β (LMX1B). There is no correlation between the type or nature of individual mutations and the severity of the phenotype. The availability of animal models, together with analysis of gene expression patterns during development, has substantiated that the range of clinically relevant signs and symptoms is greater than appreciated previously. Evidence is building that attention deficit±hyperactivity disorder and depression may be constituent parts of the syndrome. The variation in the range and severity of symptoms, and the diverse range of affected tissues, make NPS an appropriate model in which to study the effects of gene interactions on the observed phenotype.

Key Concepts:

  • NPS is a pleiotropic, clinically variable autosomal dominant disorder.

  • LMX1B is a member of a gene family primarily involved in regulating neuronal patterning.

  • Loss of function mutations in LMX1B cause NPS but do not predict disease severity.

  • Analysis of Lmx1b expression has helped explain previously unknown neural aspects of NPS.

  • Physicians should be aware of the extra‐skeletal aspects of NPS and institute appropriate monitoring and treatment.

Keywords: nail–patella syndrome; LMX1B; mutations; pleiotropy; central nervous system

Figure 1.

The ‘classic tetrad’ of NPS. (a) Nail dysplasia: Left hand upper panels, right hand lower panels. Note that dysplasia is more severe on the thumb and becomes milder from thumb to fifth finger. Note also the absence of creases over the distal interphalangeal joints. (b) Knee dysplasia. A fixed dislocation of the patella is seen on the right knee, with patellar aplasia on the left. (c) Elbow dysplasia. Note pterygia of left elbow at full extension. Note also poor development of muscle in upper arms. (d) Pelvic X‐ray showing bilateral iliac horns (arrows).

Figure 2.

Missense mutations (• below the gene) are clustered within the LIM and homeodomains of LMX1B. They always change highly conserved residues. Nonsense (X), frameshift (Δ) and splice (□) mutations, which prevent synthesis of a full‐length protein, also tend to be grouped in these regions. It is not known why there are no NPS mutations downstream of the homeodomain.

Figure 3.

Expression of Lmx1b during mouse development as determined by β‐galactosidase staining of embryos carrying the Lmx1b3′ LacZ allele (Dunston et al., ). Whole embryos were stained overnight: (a) E9.5, (b) E10.5, (c) E11.5, (d) E12.5 and (e) E13.5. For (f) E14.5 and (g–i) E15.5, embryos were partially dissected to allow for more efficient staining. (g) E15.5 forelimb. (h) E15.5 trunk and hindlimbs. (i) E15.5 head. Transverse views of the rostral spinal cord of β‐galactosidase stained Lmx1b3′ LacZ embryos; (j) E10.5, (k and l) E11.5, (m) E12.5, (n) E13.5 and (o) E15.5 embryos. Expression was analysed by β‐galactosidase staining except for (l) which is in situ hybridisation of the Lmx1b mRNA at E11.5 to be compared to panel (k). Lmx1b expression in kidney and mammary gland; (p) Kidney expression at E14.5 visualised by β‐galactosidase staining shows expression in glomeruli, (q) HandE stained section at 20X magnification showing mammary gland expression in an E15.5 embryo. Lmx1b appears to be uniformly expressed throughout the mammary gland primordium. Arrowhead: isthmus and location of Lmx1b expression at the midbrain–hindbrain junction (a); Arrow: mammary gland expression (c)100. Floor plate, fp; Central canal, cc; dorsal, D and ventral, V. Dorsal is on top for sections j–o. Reproduced with permission from McIntosh et al..



Beals RK and Eckhardt AL (1969) Hereditary onycho‐osteodysplasia (nail–patella syndrome). A report of nine kindreds. Journal of Bone and Joint Surgery (America) 51(3): 505–516.

Bergman O, Westberg L, Nilsson LG, Adolfsson R and Eriksson E (2010) Preliminary evidence that polymorphisms in dopamine‐related transcription factors LMX1A, LMX1B and PITX3 are associated with schizophrenia. Progress in Neuropsychopharmacology and Biological Psychiatry 16: 1094–1097.

Bongers EM, Gubler MC and Knoers NV (2002) Nail–patella syndrome. Overview on clinical and molecular findings. Pediatric Nephrology 17: 703–712.

Bongers EM, Huysmans FT, Levtchenko E et al. (2005) Genotype–phenotype studies in Nail–Patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. European Journal of Human Genetics 13: 935–946.

Chen H, Lun Y, Ovchinnikov D et al. (1998) Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nature Genetics 19(1): 51–55.

Cheng L, Chen CL, Luo P et al. (2003) Lmx1b, Pet‐1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype. Journal of Neuroscience 23: 9961–9967.

Diaz‐Stransky A, López‐Arvizu C, Sparrow EP et al. (2011) Serotonin and Dopaminergic System Anomalies Attributed to Lmx1b Haploinsufficiency: Understanding Symptoms of ADHD in Nail Patella Syndrome. Toronto, Canada: American Academy of Child and Adolescent Psychiatry.

Ding YQ, Marklund U, Yuan W et al. (2003) Lmx1b is essential for the development of seratonergic neurons. Nature Neuroscience 6: 933–938.

Ding YQ, Yin J, Kania A et al. (2004) Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord. Development 131: 3693–3703.

Dreyer S, Morello R, German M et al. (2000) LMX1B transactivation and expression in nail–patella syndrome. Human Molecular Genetics 9(7): 1067–1074.

Dreyer SD, Zhou G, Baldini A et al. (1998) Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nature Genetics 19: 47–50.

Dunston JA, Hamlington JD, Zaveri J et al. (2004) The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics 84: 565–576.

Dunston JA, Reimschisel T, Ding YQ et al. (2005) A neurological phenotype in nail patella syndrome (NPS) patients revealed by studies of murine Lmx1b expression. European Journal of Human Genetics 13: 330–335.

Eyaid WM, Clough MV, Root H et al. (1998) Physical mapping of the nail patella syndrome interval at 9q34: ordering of STSs and ESTs. Human Genetics 103: 525–526.

Guo C, Qiu HY, Huang Y et al. (2007) Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Development 134: 317–325.

Hobert O and Westphal H (2000) Functions of LIM‐homeobox genes. Trends in Genetics 16: 75–83.

Iannotti CA, Inoue H, Bernal E et al. (1997) Identification of a human LMX1 (LMX1.1)‐related gene, LMX1.2: tissue‐ specific expression and linkage mapping on chromosome 9. Genomics 46: 520–524.

Kieser W (1939) Die Sog. Flughaut beim Menschen. Zeitschrift für menschliche Vererbungs‐ und Konstitutionslehre 23: 594.

Krawchuk D and Kania A (2008) Identification of genes controlled by LMX1B in the developing mouse limb bud. Developmental Dynamics 237: 1183–1192.

Lemley KV (2009) Kidney disease in Nail–Patella syndrome. Pediatric Nephrology 24: 2345–2354.

Lichter PR, Richards JE, Downs CA et al. (1997) Cosegregation of open‐angle glaucoma and the Nail–Patella syndrome. American Journal of Ophthalmolology 124: 506–515.

Little E (1897) Congenital absence or delayed development of the patella. Lancet 2: 781–784.

Liu P and Johnson RL (2010) Lmx1b is required for murine trabecular meshwork formation and for maintenance of corneal transparency. Developmental Dynamics 239: 2161–2171.

López‐Arvizu C, Sparrow EP, Strube MJ et al. (2010) Increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in nail–patella syndrome: POTENTIAL association with LMX1B loss‐of‐function. American Journal of Medical Genetics B 156: 59–66.

Marini M, Bocciardi R, Gimelli S et al. (2010) A spectrum of LMX1B mutations in nail–patella syndrome: new point mutations, deletion, and evidence of mosaicism in unaffected parents. Genetics in Medicine 12: 431–439.

McIntosh I, Dreyer SD, Clough MV et al. (1998) Mutation analysis of LMX1B gene in nail–patella syndrome patients. American Journal of Human Genetics 63: 1651–1658.

McIntosh I, Dunston JA, Liu L, Hoover‐Fong JE and Sweeney E (2005) Nail patella syndrome revisited: 50 years after linkage. Annals of Human Genetics 69: 349–363.

Mcintosh I, López‐Arvizu C, Diaz‐Stransky A et al. (2011). Increased incidence of attention deficit hyperactivity disorder (ADHD) in children with nail patella syndrome. Presented at the 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics, Montreal, Canada.

Mease PJ, Dundon K and Sarzi‐Puttini P (2011) Pharmacotherapy of fibromyalgia. Best Practice and Research: Clinical Rheumatology 25: 285–297.

Miner J, Morello R, Andrews K et al. (2002) Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. Journal of Clinical Investigation 109(8): 1065–1072.

Morello R, Zhou G, Dreyer S et al. (2001) Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nature Genetics 27: 205–208.

Morita T, Laughlin LO, Kawano K et al. (1973) Nail‐patella syndrome. Light and electron microscopic studies of the kidney. Archives of Internal Medicine 131: 271–277.

Park S, Jamshidi Y, Vaideanu D et al. (2009) Genetic risk for primary open‐angle glaucoma determined by LMX1B haplotypes. Investigative Ophthalmology and Visual Science 50: 1522–1530.

Pressman CL, Chen H and Johnson RL (2000) LMX1B, a LIM homeodomain class transcription factor, is necessary for normal development of multiple tissues in the anterior segment of the murine eye. Genesis 26: 15–25.

Renwick JH and Lawler SD (1955) Genetical linkage between the ABO and nail–patella loci. Annals of Human Genetics 19: 312–331.

Riddle RD, Ensini M, Nelson C et al. (1995) Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb. Cell 83: 631–640.

Rohr C, Prestel J, Heidet L et al. (2002) The LIM‐homeodomain transcription factor Lmx1b plays a crucial role in podocytes. Journal of Clinical Investigation 109(8): 1073–1082.

Smidt M, Asbreuk C, Cox J et al. (2000) A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nature Neuroscience 3(4): 337–341.

Song NN, Xiu JB, Huan Y et al. (2011) Adult raphe‐specific deletion of Lmx1b leads to central serotonin deficiency. Public Library of Science ONE 6: e15998.

Sweeney E, Fryer A, Mountford R, Green A and McIntosh I (2003) Nail patella syndrome: a review of the phenotype aided by developmental biology. Journal of Medical Genetics 40: 153–162.

Thansemm I, Nakamura K, Anitha A et al. (2011) Association of transcription factor gene LMX1B with autism. Public Library of Science ONE 6: e23738.

Towers AL, Clay CA, Sereika SM, McIntosh I and Greenspan SL (2005) Skeletal integrity in patients with nail patella syndrome. Journal of Clinical Endocrinology and Metabolism 90: 1961–1965.

Turner JW (1933) An hereditary arthrodysplasia associated with hereditary dystrophy of the nails. Journal of the American Medical Association 100: 882–884.

Vollrath D, Jaramillo‐Babb VL, Clough MV et al. (1998) Loss of function mutations in the LIM homeodomain gene, LMX1B, in nail‐patella syndrome. Human Molecular Genetics 7: 1091–1098.

Yan CH, Levesque M, Claxton S, Johnson RL and Ang SL (2011) Lmx1a and lmx1b function cooperatively to regulate proliferation, specification, and differentiation of midbrain dopaminergic progenitors. Journal of Neuroscience 31: 12413–12425.

Zhao ZQ, Chiechio S, Sun YG et al. (2007) Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. Journal of Neuroscience 27: 6045–6053.

Zhao ZQ, Scott M, Chichio S et al. (2006) Lmx1b is required for maintenance of central serotonergic neurons and mcie lacking central serotonergic system exhibit normal locomotor activity. Journal of Neuroscience 26: 12781–12788.

Further Reading

Dai JX, Johnson RL and Ding YQ (2009) Manifold functions of the nail–patella syndrome gene Lmx1b in vertebrate development. Development Growth Differentiation 51: 241–250.

Hoover‐Fong J, McIntosh I and Sweeney E (2009) Nail‐Patella Syndrome. eMedicine from WebMD. Updated 20 Oct 2009. Available at:‐overview.

Lee B and Morello R (2004) LMX1B and the nail patella syndrome. In: Epstein CJ, Erickson RP and Wynshaw‐Boris A (eds) Inborn errors of development, pp. 615–624. New York: Oxford University Press.

Sweeney E, Hoover‐Fong JE and McIntosh I (2009) Nail–patella syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K and Adam MP (eds) GeneReviews™ [Internet], p. 1993. Seattle (WA): University of Washington, Seattle.

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McIntosh, Iain(Nov 2012) Molecular Genetics of Nail–Patella Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024340]